Glycotargeting therapeutics
Glycotargeting therapeutics are useful in the treatment of transplant rejection, autoimmune disease, food allergy, and immune response against a therapeutic agent.
1. A composition comprising a compound of Formula 1:
where:
m is an integer from 1 to 100;
X comprises a self-antigen which induces an unwanted immune response;
where Y comprises one or more structures represented by one or more of the following Formulae:
where:
the left bracket “(” indicates the bond between X and Y;
the right or bottom bracket and “)” indicates the bond between Y and Z;
n, where present, is an integer from 1 to 100;
p, where present, is an integer from 2 to 150;
q, where present, is an integer from 1 to 44;
R 8 , where present, is —CH 2 — or —CH 2 —CH 2 —C(CH 3 )(CN)—; and
R 9 , where present, is a direct bond or —C(O)—NH—CH 2 —CH 2 —; and
Z comprises one or more liver-targeting moieties.
2. The composition of claim 1 where:
n, where present, is 40 to 80;
p, where present, is 10 to 100;
q, where present, is 3 to 20;
R 8 , where present, is —CH 2 —CH 2 —C(CH 3 )(CN)—; and
R 9 , where present, is —C(O)—NH—CH 2 —CH 2 —,
Z is galactose or N-acetylgalactosamine conjugated at its C1.
3. The composition of claim 1 wherein X comprises a synthetic self-antigen against the endogenous version of which patients develop an unwanted immune response.
4. The composition of claim 1 , wherein X is selected from the group consisting of insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, glucose-6 phosphatase 2, insulinoma-associated protein 2, and insulinoma-associated protein 213.
5. The composition of claim 1 , wherein X is selected from the group consisting of myelin basic protein, myelin oligodendrocyte glycoprotein, myelin proteolipid protein, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17.
6. The composition of claim 1 , wherein X is transglutaminase.
7. The composition of claim 1 , where Y further comprises the following group:
8. The composition of claim 1 , wherein Z comprises galactose, galactosamine or N-acetylgalactosamine.
9. The composition of claim 8 , wherein Z is conjugated at its C1, C2 or C6 to Y.
10. The composition of claim 1 , wherein Y is prepared using N-hydroxysuccinamidyl linkers, malaemide linkers, vinylsulfone linkers, pyridyl di-thiol-poly(ethylene glycol) linkers, pyridyl di-thiol linkers, n-nitrophenyl carbonate linkers, NETS-ester linkers, or nitrophenoxy poly(ethylene glycol)ester linkers.
11. The composition of claim 1 where Y comprises Formula Ym.
12. The composition of claim 11 , wherein X is a synthetic self-antigen against the endogenous version of which patients develop an unwanted immune response.
13. The composition of claim 11 , wherein Z is N-acetylgalactosamine conjugated at its C1 position.
14. The composition of claim 11 , wherein Z is galactose conjugated at its C1 position.
15. The composition of claim 11 , wherein n is 40 to 80; and p is 10 to 100.
16. The composition of claim 11 , wherein X is associated with an autoimmune disease selected from the group consisting of Type I diabetes, multiple sclerosis, rheumatoid arthritis, vitiligo, uveitis, pemphigus vulgaris and neuromyelitis optica.
17. A compound represented by Formula 1:
where:
m is an integer from 1 to 100;
X comprises a self-antigen, wherein the self-antigen is capable of inducing an unwanted immune response;
Y comprises a linker moiety comprising one or more of the following Formulae:
where:
the left bracket “(” indicates the bond between X and Y;
the right or bottom bracket and “)” indicates the bond between Y and Z;
n, where present, is an integer from 1 to 100;
p, where present, is an integer from 2 to 150;
q, where present, is an integer from 1 to 44;
R 8 , where present, is —CH 2 — or —CH 2 —CH 2 —C(CH 3 )(CN)—; and
R 9 , where present, is a direct bond or —C(O)—NH—CH 2 —CH 2 —; and
Z comprises one or more liver-targeting moieties.
18. The compound of claim 17 , wherein the self-antigen is selected from the group consisting of insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, glucose-6 phosphatase 2, insulinoma-associated protein 2, and insulinoma-associated protein 213.
19. The compound of claim 17 , wherein X is associated with an autoimmune disease selected from the group consisting of Type I diabetes, multiple sclerosis, rheumatoid arthritis, vitiligo, uveitis, pemphigus vulgaris and neuromyelitis optica.
20. The compound of claim 17 , wherein X is selected from the group consisting of myelin basic protein, myelin oligodendrocyte glycoprotein, myelin proteolipid protein, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17.
21. The compound of claim 17 , wherein Z comprises galactose, galactosamine or N-acetylgalactosamine.
22. The compound of claim 21 , comprising Z conjugated at its C1, C2 or C6 to Y.
23. The compound of claim 22 , wherein X is associated with Type I diabetes.
24. The compound of claim 22 , wherein X is associated with multiple sclerosis.
25. The compound of claim 22 , wherein Y is Ym.
26. The compound of claim 21 , wherein Z is N-acetylgalactosamine conjugated at its C1 position.